Polycyclic gamma-pyrone-3-carboxaldehyde derivatives

ABSTRACT

Novel polycyclic gamma-pyrone derivatives having a carboxaldehyde group on the 3-position and optionally substituted on the 5, 6, 7, 8, 9 or 10 positions with a hydroxy, lower alkyl or lower alkoxy group are disclosed, as well as the corresponding N-substituted, formyl imine derivatives thereof. These compounds, and pharmaceutical compositions containing these compounds, are useful for the treatment of allergic conditions and for the treatment of hyperacidity.

United States Patent Kaminsky, deceased et al.

June 3, 1975 POLYCYCLIC GAMMA-PYRONE-S-CARBOXALDEHYDE DERIVATIVES Inventors: Daniel Kaminsky, deceased, late of Parsippany, N.J., by Bernice R. Kaminsky, administratrix; Sylvester Klutchko, Hackettstown; Maximilian Von Strandtmann, Rockaway, both of NJ.

Assignee: Warner-Lambert Company, Morris Plains, NJ.

Filed: June 19, 1974 Appl. No.: 480,647

Related US. Application Data Continuation-impart of Ser. No. 352,135, April 18, 1973, abandoned.

US. Cl 260/345.2; 424/283 Int. Cl C07d 7/32 Field of Search 260/3452 References Cited FOREIGN PATENTS OR APPLICATIONS 6/1971 Belgium OTHER PUBLICATIONS Eiden et al., Arch der Pharm., Vol. 300, 806, (1967). Reynolds et al., J. Het. chem., Vol. 6, pp. 375-377, (1969).

Harnische, Ann. der Chemie, Vol. 765, pp. 8-14, (1972),

Nohara et al,, Tetrahedron Letters, No. 22, pp. 1995-1998, (1973).

Primary Examiner.lohn M. Ford Attorney, Agent, or FirmAlbert H. Graddis; Frank S. Chow; Anne M. Kelly [5 7 ABSTRACT 13 Claims, N0 Drawings POLYC YCLIC GAMMA-PYRONE-3-CARBOXALDEHYDE DERIVATIVES CROSS REFERENCE TO RELATED APPLICATION I This application is a continuation-in-part of U.S.Ser. No. 352,135, filed Apr. 18, I973, now abandoned.

SUMMARY OF THE INVENTION This invention relates to novel polycyclic gamma-pyrone-3-carboxaldehyde derivatives having the formula I:

CHO

wherein R represents hydrogen, hydroxy, lower alkyl, or lower alkoxy and the Z ring has one of the following structures:

and the corresponding N-substituted, formyl imine derivatives thereof. These novel compounds, and novel pharmaceutical compositions containing these compounds, are useful for the treatment of allergic conditions and for the treatment of hyp r y- In addition,

POunals of the formula I wherein the Z ring represents:

and R is as defined above, and pharmaceutical compositions containing these last-mentioned compounds, are useful for the treatment of allergic conditions and for the treatment of hyperacidity.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention have the general formula I:

wherein R represents hydrogen, hydroxy, lower alkyl, or lower alkoxy and the Z ring has one of the following structures:

andthe corresponding N-substituted, formyl imine derivatives thereof.

Derivatives of 3-formyl-gamma-pyrones, such as oximes, semicarbazones, thiosemicarbazones, acetals and hydrazones, are also the subject of this invention.

As a particularly active class of compounds, there may be mentioned those compounds having formula I above, wherein the Z ring has the structure (a) and R represents hydrogen. hydroxy, methyl or methoxy, and the corresponding N-substituted, formyl imine derivatives thereof. Another particularly preferred class of compounds are those having formula I above, wherein the Z ring has the structure (1)), (c), (d). or (e) and R represents hydrogen.

The novel compounds of this invention may be prepared by either of two different procedures. One process, described more fully in co-pending application Ser. No. 351,912, filed Apr. 18, 1973, now U.S. Pat. No. 3,862,144, relates to the preparation of compounds of the general formula 1 wherein the Z ring has the structure (a) or (b): such compounds are represented in formula 11:

wherein R represents hydrogen, hydroxy, lower alkyl, or lower alkoxy, and n represents 1 or 2. Compounds of the formula 11 are prepared by treating a compound of the formula III:

wherein R and n are as described above, with an acetic anhydride and a boron trifluoride compound, preferably boron trifluoride etherate, to provide an intermediate of the formula IV:

wherein R represents hydrogen, lower alkyl, or lower alkoxy and the Z ring has one of the following structures:

Compounds of the general formula V are prepared by oxidizing a compound of the formula VI:

CH OH wherein R and the Z ring are as defined above, using an oxidizing agent selected from the group consisting of sodium dichromateglacial acetic acid, concentrated nitric acid, and potassium persulfate. Starting materials VI and their precursors (as well as various derivatives thereof, containing one or more substituents on the naphtho ring) are described more fully in co-pending U.S. Ser. No. 112,765, filed Feb. 4, 1971, now abandoned; and in continuation-in-part (of said Ser. No. 1 12,765), application Ser. No. 309,329, filed Nov. 24, 1972, now U.S. Pat. No. 3,798,240; in continuation-inpart (of said Ser. No. 309,329), application Ser. No. 387,861 filed Aug. 13, 1973; and U.S. application Ser. No. 392,152, filed Aug. 27, 1973.

The above-mentioned compounds VI are prepared by reacting correspondingly substituted compounds having the formula VII:

0H VII wherein R and Z are as defined above, with 2 moles of formaldehyde under basic conditions to obtain an intermediate compound having the formula V111:

VIII

Compounds having the formula VII above are prepared by (A) reacting dimethyl sulfoxide with sodium hydride in an inert solvent; (B) adding to reaction mixture (A) an appropriately substituted orthohydroxynaphthoate (or tetrahydro derivative thereof): (C) maintaining the reaction mixture of (B) at a temperature of up to 50C; (D) reducing the solubility of the sodium salt reaction product of (C) by the addition of a non-polar solvent; and (E) collecting the precipitate formed. A similar preparation has been reported by Becker et al., J.A.C.S. 85: 3410 (1963).

Substituted and unsubstituted l-hydroxy-2- naphthoates (Ber. 2700 1 887), substituted and unsubstituted 3-hydroxy-2-naphthoates (Ber. 3635 (1892), and the corresponding 5,6,7,8tetrahydro derivatives thereof (Ann. 426: 147, 158 (1922) are known or easily prepared by known methods.

Compounds of the general formula I wherein R represents hydrogen and the Z ring has the structure (f):

are disclosed in J. Het. Chem. 6: 375-377, June 1, 1969; no particular therapeutic activity for such compounds is reported in this reference. However, these compounds and their derivatives represented by the formula IX:

CHO

wherein R represents hydrogen, hydroxy, lower alkyl or lower alkoxy, have demonstrated, quite surprisingly, useful activity in the treatment of allergic conditions and in the treatment of hyperacidity.

Thus, the polycyclic gamma-pyrone-3- carboxaldehyde derivatives of this invention having formula I prepared by either of the two methods described above (and compounds of the general formula IX) have been found to reduce histaminic responses to antigen challenge by inhibiting. antibody-antigen reactions in mammals such as rats or guinea pigs upon oral or parenteral administration. When tested in accordance with the procedure of Mota, Life Sciences, 7, 465, (1963) and Ovary, Proc. Soc. Exptl. Biol. Med, 81, 584, (1952) therapeutic compositions containing these compounds are effective at dosages of 5 mg to 50 mg/kg of body weight.

Pharmaceutical compositions containing the compounds of formula I are therefore useful in the management of allergic reactions such as bronchial asthma. To treat bronchial asthma, a dose of 5 mg to 50 mg/kg, administered orally or parentereally is suggested; in addition, aerosol administration of lower doses may be used. The dosage may be varied depending upon severity of the condition and the weight, age and sex of the patient being treated.

In use the compounds of formula I and IX may be combined with a parenterally acceptable vehicle, such as a gum tragacanth saline suspension. to provide dosage forms suitable for parenteral administration; or they may be combined with pharmaceutical diluents such as lactose, cornstarch, and the like and formulated into tablet or capsule dosage forms. In order to enhance their therapeutic spectrum, the compounds of formula I may be combined with sympathomimetic agents such as isoprenaline or combined with steroids such as cortisone and its derivatives.

The compounds of formula I and IX also exhibit antisecretory effects and are therefore useful in relieving gastric hyperacidity. Gastric hyperacidity has generally been described as a factor which contributes to peptic ulcer. The compounds of formula I, when administered to mammals in a manner as described below, have been found to inhibit the gastric secretion of hydrochloric acid and are therefore effective in eliminating the resulting acidity in the stomach.

At a dosage of 20 mg/kg, administered intraperitoneally, the subject compositions are effective in reducing gastric acidity in the pylorus ligated rat when tested according to the procedure of H. Shay, Gastroenterology, 5, 43, (1945).

Pharmaceutical compositions containing the compounds of formula I are thus indicated in the management of gastric hyperacidity and the treatment of pep-- tic ulcer resulting from such hyperacidity. For parenteral administration, the pharmaceutical compositions containing the compounds of formula I may be administered as aqueous suspensions for intramuscular injection. These are prepared, for example, by suspending the active ingredient in sterile water and packaging in ampules so as to provide a concentration of 1,000 mg of the active ingredient per dosage unit.

In all of the above represented formulas I through IX, definitions may be more fully described as follows: the term lower alkyl is meant to include lower aliphatic hydrocarbons having 1 to 4 carbon atoms in the carbon chain, such as methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. This definition for lower alkyl also applies to the lower alkyl portion of lower alkoxy.

To further illustrate the practice of this invention, the following examples are included:

EXAMPLE I Preparation of 2,2-difluoro-5,6-dihydro-4-methylnaphthol l ,2-e]- 1,3,2-dioxaborin-Method A Boron trifluoride etherate g.-0.7 mole) is added to a mixture of 73 g. (0.5 mole) a-tetralone in 204 g. (2.0 mole) of acetic anhydride. The mixture is heated on a steam bath for 2 hours (permitting volatiles to escape) and then gently refluxed for 1 hr. After standing overnight the mixture is triturated with cold ethyl acetate and filtered. The product is washed with ethyl ether and dried yielding 1 12 g. (9594 1 of greenish crystals; mp 156l59C. The analytical sample (from ethyl acetate) melted at 159-16()C.

Anal. Calcd: C H BF O C. 61.07: H. 4.71); F. 16.10. Found: C. 61.14; H. 4.72; F. 16.12.

EXAMPLE ll (9% I C i= Preparation of 2,2-difluoro-5.6-dihydro-4.6-dimethylnaphth[1,2- e]1.3;2-dioxaborin Starting with 4-methyl-a-tetralone and using method A of Example 1. 2.2-difluoro-5,6-dihydro-4.6- dimethy1naphtho[1.2-e]-1,3.2-dioxaborin is obtained having an mp of 120122C.

Anal. Calcd: C H BF O z C. 62.44; H. 5.24; F. 15.20. Found: C. 62.47; H. 5.24; F. 15.21.

EXAMPLE 11] EXAMPLE IV CH O Preparation of 2.2-dit'1uoro-5.6-dihydro-8-methoxy4- meth vlnaphthol 1.2-0]1.3.2-dioxahorin Starting with 6-methoxy-u-tctralone and using method A of Example 1. 2.2-difluoro-5.6-dihydro-8- mcthox \'-4-methylnaphthol 1.2-0]1.3.2-dioxaborin is obtained having an mp of l176C.

Anal. Calcd: C H BF O C. 58.69; H. 4.92; F. 14.28. Found: C. 58.36: H. 4.81: F, 14.23.

EXAMPLE V Preparation of 2,Z-difluoro-S.6-dihydro-7-acetoxy-4- methylnaphtho[ 1.2-e] 1.3.2-dioxaborin Starting with S-acetoxy-a-tetralone and using Method A of Example I, 2.2-difluoro-5.6-dihydro-7- acetoxy-4-methylnaphthol 1,2-e] 1.3,2-di0xaborin is obtained having an mp of 159-160C.

Anal. Calcd: C H BF O C. 57.18. H. 4.46; F, 12.92. Found: C, 56.98; H. 4.41; F. 13.13.

EXAMPLE V1 Preparation of 2.2-difluoro-5.6-dihydro-9-nitro-4-methylnaphtho[ 1.2- e] 1.3.2-dioxaborin Starting with 7-nitro-a-tetralone and using method A of Example 1, 2.2-difluoro-5.6-dihydro-9-nitro-4- methylnaphthol 1.2-e] l .3.2-dioxaborin is obtained having an mp of l76191C.

Anal. Calcd: C H,.,BF NO C. 51.29: H. 3.59; F. 13.52. Found: C. 51.38; H. 3.53; F. 13.63.

EXAMPLE V11 Preparation of 2,2-difiuoro-4-methyl-5 H-indeno[ 2,3-e1dioxaborin Starting with indanone and using method A of Example l, 2,2-difluoro-4-methyl5H-indenol 2 ,3- e]dioxaborin is obtained having an mp of 233-235C (dec.).

Anal. Calcd: *CHHQBFQOQZ C, 59.51; H, 4.09; F, 17.12. Found: C, 59.64; H, 4.12; F, 16.92.

EXAMPLE VIII Method B-Preparation of 5,6-dihydr-4-oxo-4H-naphtho[ 1,2-b1pyran-3- carboxaldehyde 202 g. (89.5%) dark brown product; mp 153-l56C.

The analytical sample (from acetonitrile) melted at 154-156C.

Anal. Calcd for C llmO z C, 74.33; H, 4.46; O, 21.22. Found: C, 74.33; H, 4.41; O, 21.05.

EXAMPLE IX Preparation of 5,6-drhydro-6-methyl-4-oxo-4H-nap l ]p 3-carboxaldehyde Starting with 2,2-difluoro-5,6-dihydro-4.6- dimethylnaphtho[1,2-e] 1,3,2-dioxab0rin and usin method 8 of Example VIII, 5,6-dihydro-6-methy oxo-4H-naphtho[ l,2-b]pyran-3-carboxaldehyde is obtained having an mp of 146 148C.

Anal. Calcd: c n o z c, 74.99; H, 5.03; Found: C, 74.90; H, 5.07; O, 19.83.

EXAMPLE X CHO ' Preparation of 5 ,6-dihydro-7-hydroxy-4-oxo-4H-naphtho[ 1,2- b]pyran-3-carboxaldehyde Starting with 2,2-difluoro-5,6-dihydro-7-acetoxy-4- methylnaphtho[ 1,2-e] l ,3,2-dioxaborin and using method B of Example VIII, 5,6-clihydro-7-hydroxy-4- oxo-4l-l-naphtho[ 1 ,2-b]pyran-3-carboxaldehyde is obtained having an mp of 255 256C. (dec.)

Anal. Calcd: C H O c, 69.42; H, 4.16; 0, 26.42.

Found: C, 69.58; H, 5.20; O, 26.68.

EXAMPLE XI Preparation. of 5,6-dihydro-7 hydroxy-3-( N-veratrylformimid naphtho[ l,2-b]pyran-4-one monohy The product of Example X is reacted with veratrylamine to obtain 5,6-dihydro-7-hydroXy-3-( vcratrylformimidoyl )-4l-l-naphtho[ l,2-b]pyran-4-0n monohydrate having an mp of 157l59C.

Anal. Calcd: C I-[ 0 1911 0 C, 67.46; H, 5.66; O, 23.45; N, 3.42. Found: C, 67.35; H, 5.75; O, 23.08; 3.48.

EXAMPLE XII Preparation of 5,6-dihydrO-7-methox -4 x -4H-naphthol 1,2- Pyran-3-carboxaldehyde Starting with 2,2-difluoro-5,6-dihydro-7-methoxy 4- methylnaphtho[ 1,24 1 1 gidioxaborin d using method B of Example VIII, 5 6.dih dro-7-metho xy-4- 0xo-4H-naphth0[ l,Z-b]- 3 rb xaldehyde IS obtained having an mp of 201-202C.

Anal. Calcd: C H, O,: C, 70.30; H, 4.72. Found: C, 70.23; H. 4.73.

EXAMPLE XIII CHO Preparation of 5,6-dihydro-8-methoxy-4-oxo-4H-naphtho[ 1,2- b]pyran-3-carboxaldehyde Starting with 2,2-difluoro-5,6-dihydro-8-methoxy-4- methy1naphtho[ l,2-e]1,3,2-dioxaborin and using method B of Example VIII, 5,6-dihydro-8-methoxy-4- oxo-4H-naphthol1,2-b]pyran-3-carboxaldehyde is obtained having an mp of I86187C. (dec.)

Anal. Calcd: C H, O C, 70.30; H, 4.72; O, 24.98. Found: C, 70.11; H, 4.77; O, 24.78.

EXAMPLE XIV CHO Method C: Preparation of 4-oxo-4I-I-naphtho[2,3-b]pyran-3-carboxaldehyde A slurry of 1.6g (0.007 mole) of 3-(hydroxymethyl)- 4I-I-naphtho[2,3-b]pyran-4-one in 10 ml of glacial acetic acid is added to a stirred solution of 2.11 g (0.007 mole) of sodium dichromate dihydrate, keeping the temperature at 40C. with mild cooling. After the initial exotherm, the reaction is stirred at room temperature overnight. Water (100 ml) is added and the resulting turbid solution is heated to 75C. to generate a precipitate. The cooled mixture is filtered and the crude product 1.4g) is purified by filtration of a methylene chloride solution through a layer of silica gel, wt. 0.22g (14%), mp 2152l8C. Recrystallization from ethylacetate gives pure aldehyde; mp 220222C.

Anal. Calcd: C H O C, 75.00; H, 3.60. Found: C, 74.88; H, 3.67.

EXAMPLE XV H CH0 Method C: Preparation of 3-Formyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]py a 4-one A mixture of 2.3g (0.01 mole) of 3-(hydroxymethyl)- 6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-4-one and 15 ml of glacial acetic acid is added to a solution of 298g (0.01 mole) of sodium dichromate dihydrate in 15 ml of glacial acetic acid, keeping the temperature at about 50C. with mild cooling. After 15 minutes, the reaction is heated at 60C. for 15 minutes. water (100 ml) is added and the mixture is heated at 50C. for 5 minutes. The separated solid is filtered, washed with water and dried; wt. 1.6g mp l20-l23C. Purification is effected by dissolving in methylene chloride and filtering through a layer of silica gel. The pure aldehyde is obtained by removal of solvent from the filtrate; mp l28l30C.

Anal. Calcd: C H, O C, 73.67; H, 5.30. Found: C, 73.54; H, 5.20.

EXAMPLE XVI Method C: Preparation of 3-formyl-7,8,9,10-tetrahydro-4I-l-naphthol 1,2- b]pyran-4-one This compound is prepared by adding a mixture of 23.0 g (0.1 mole) of 3-(hydroxymethyl)-7,8,9,10- tetrahydro-4H-naphtho[1,2-b]pyran-4-one and 150 ml of glacial acetic acid to a solution of 29.8 g (0.1 mole) of sodium dichromate dihydrate in 150 ml of glacial acetic acid, keeping the temperature at about 50C with cooling. After the initial exotherm, the reaction is heated at 60C for /2 hour, water l-liter) is added, and the mixture is heated at C for about V2 hour to generate a precipitate. The cooled mixture is filtered and the crude product is purified by dissolving in methylene chloride and filtering through a layer of silica gel. The aldehyde is obtained by removal of solvent from the filtrate.

EXAMPLE XVII CI-IO Method C: Preparation of 3-formyl-4H-naphtho[ 1 ,2-b]pyran-4-one A solution 8.44 g (0.028 mole) of sodium dichromate dihydrate in 30 ml of glacial acetic acid is added to a stirred mixture of 6.4 g (0.028 mole) of (hydroxymethyl)-4H-naphtho[ 1,2-b] pyran-4-one and 40 ml glacial acetic acid. The reaction is exothermic. The temperature is prevented from going over 50C with cooling. After /2 hour at 3550C the solution 18 heated to 70C for /2 hour, water (200 ml) is added. The mixture is cooled and the separated crude solid 15 collected. Purification is effected by filtration of a methylene chloride solution through a layer of silica gel. in this fashion 1.0 g (16%) of pure aldehyde is obtained, mp l78l80C.

Anal. Calcd: C I-L C, 74.99; H, 3.60. Found: C, 75.08; H, 3.74.

We claim:

1. A compound of the formula I:

wherein R represents hydrogen, hydroxy, lower alkyl, or lower alkoxy and the Z ring has one of the following structures:

and the corresponding N-substituted, 3-formimide derivatives thereof.

2. A compound according to claim 1 wherein the Z ring has the (a) structure and R represents hydrogen, hydroxy, methyl or methoxy, and the corresponding N- substituted, 3-formimide derivatives thereof.

3. A compound according to claim 1 wherein the Z ring has the structure ([2), (c), (d), or (e) and R represents hydrogen.

4. A compound according. to claim 1 which is 5,6- dihydro-4-oxo-4H-naphtho[ l,2-b]pyran-3- carboxaldehyde.

5. A compound according to claim 1 which is 5,6- dihydro-6-methyl-4-oxo-4H-naphtho[ l,2-b]pyran-3- carboxaldehyde.

6. A compound according to claim 1 which is 5,6- dihydr0-7-hydroxy-4-oxo-4H-naphtho[ l,2-b]pyran-3- carboxaldehyde.

7. A compound according to claim 1 which is 5,6- dihydro-7-hydroxy-3-(N-veratryl formimidoyl)-4H- naphtho[1,2-b]pyran-4-one and its monohydrate.

8. A compound according to claim 1 which is 5,6- dihydro-7-methoxy-4-oxo-4H-naphtho[1,2-b]pyran-3- carboxaldehyde.

9. A compound according to claim 1 which is 5,6- dihydro-8-methoxy-4-oxo-4H-naphtho[ l,2-b]pyran-3- carboxaldehyde.

10. A compound according to claim 1 which is 4-oxoindeno[3,2-b]pyran-3(5H)-carboxaldehyde.

11. A compound according to claim 1 which is 4-oxo- 4H-naphtho[2,3-b]pyran-3-carboxaldehyde.

12. A compound according to claim 1 which is 6,7,8,- 9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-3- carboxaldehyde.

13. A compound according to claim 1 which is 7,8,9,- lO-tetrahydro-4-oxo-4H-naphtho[ l ,2-b]pyran-3- carboxaldehyde. 

1. A COMPOUND OF THE FORMULA I:
 1. A compound of the formula I:
 2. A compound according to claim 1 wherein the Z ring has the (a) structure and R represents hydrogen, hydroxy, methyl or methoxy, and the corresponding N-substituted, 3-formimide derivatives thereof.
 3. A compound according to claim 1 wherein the Z ring has the structure (b), (c), (d), or (e) and R represents hydrogen.
 4. A compound according to claim 1 which is 5,6-dihydro-4-oxo-4H-naphtho(1,2-b)pyran-3-carboxaldehyde.
 5. A compound according to claim 1 which is 5,6-dihydro-6-methyl-4-oxo-4H-naphtho(1,2-b)pyran-3-carboxaldehyde.
 6. A compound according to claim 1 which is 5,6-dihydro-7-hydroxy-4-oxo-4H-naphtho(1,2-b)pyran-3-carboxaldehyde.
 7. A compound according to claim 1 which is 5,6-dihydro-7-hydroxy-3-(N-veratryl formimidoyl)-4H-naphtho(1,2-b)pyran-4-one and its monohydrate.
 8. A compound according to claim 1 which is 5,6-dihydro-7-methoxy-4-oxo-4H-naphtho(1,2-b)pyran-3-carboxaldehyde.
 9. A compound according to claim 1 which is 5,6-dihydro-8-methoxy-4-oxo-4H-naphtho(1,2-b)pyran-3-carboxaldehyde.
 10. A compound according to claim 1 which is 4-oxo-indeno(3,2-b)pyran-3(5H)-carboxaldehyde.
 11. A compound according to claim 1 which is 4-oxo-4H-naphtho(2, 3-b)pyran-3-carboxaldehyde.
 12. A compound according to claim 1 which is 6,7,8,9-tetrahydro-4-oxo-4H-naphtho(2,3-b)pyran-3-carboxaldehyde. 